当前位置： SCI文献检索 > MOLECULAR PHARMACOLOGY期刊下所有文献 > Effects of substituents on the cytosolic receptor-binding avidities and aryl hydrocarbon hydroxylase induction potencies of 7-substituted 2,3-dichlorodibenzo-p-dioxins. A quantitative structure-activity relationship analysis.

Effects of substituents on the cytosolic receptor-binding avidities and aryl hydrocarbon hydroxylase induction potencies of 7-substituted 2,3-dichlorodibenzo-p-dioxins. A quantitative structure-activity relationship analysis.

Abstract：

:The binding affinities of 16 7-substituted 2,3-dichlorodibenzo-p-dioxins for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cytosolic receptor protein from male Wistar rats have been determined. The EC50 value for each compound was estimated by competitive displacement of [3H]TCDD and the data illustrated that the differences between competitive ligands were dependent on the substituent (X) group. The EC50 value for 7-trifluoromethyl-2,3-dichlorodibenzo-p-dioxin was 1.95 X 10(-8) M and was greater than 1000-fold more active than 7-amino-2,3-dichlorodibenzo-p-dioxin (EC50 = 2.88 X 10(-5) M). Multiple parameter linear regression analysis of the data for 14 different compounds gave the following equation: log (1/EC50) = 1.24 pi + 6.11. This demonstrated that the binding affinity was linearly dependent on the lipophilicity (pi) of the 7-X-group. This contrasted with a comparable analysis of the substituent effects on the binding of 13 4'-substituted 2,3,4,5-tetrachlorobiphenyls to the cytosolic receptor which showed that the lipophilicity, electronegativity, and hydrogen-bonding capacity were important physicochemical determinants which facilitated binding to the receptor protein. These data suggest that the halogenated dibenzo-p-dioxins and biphenyls may interact with different binding sites on the receptor or they may bind to the same site but exert different conformational effects on the receptor protein. For the 7-X-2,3,-dichlorodibenzo-p-dioxins, there was not a rank order correlation between receptor-binding EC50 values and the induction of aryl hydrocarbon hydroxylase (AHH) or ethoxyresorufin O-deethylase in rat hepatoma H-4-II E cells in culture. However, the data could be correlated with an estimate of substituent width, the STERIMOL factor (B5), i.e., log (AHH) = 1.29 log (binding) + 2.19 delta B5 - 1.31 (delta B5)2 - 1.48. The importance of a steric factor in the correlation between receptor binding and AHH induction for substituted dibenzo-p-dioxins and halogenated biphenyls is consistent with a structure-dependent conformational change(s) in the receptor protein:ligand complex after the initial binding event. Presumably, this latter process is associated with the steps involving interactions between the ligand:receptor complex and nuclear binding sites.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Denomme MA,Homonoko K,Fujita T,Sawyer T,Safe S

subject

Has Abstract

pub_date

1985-06-01 00:00:00

pages

656-61

issue

eissn

0026-895X

issn

1521-0111

journal_volume

pub_type

杂志文章

在线工具

Effects of substituents on the cytosolic receptor-binding avidities and aryl hydrocarbon hydroxylase induction potencies of 7-substituted 2,3-dichlorodibenzo-p-dioxins. A quantitative structure-activity relationship analysis.